Despite advances in post-surgical chemotherapy for ovarian cancer, nearly 90% of advanced cases will develop progressive disease that is refractory to salvage chemotherapy regimens. In response to the need for alternative treatments that prevent disease recurrence or progression, tumor-specific immunologic intervention has received some attention.
TADG-12 is a serine protease highly expressed in ovarian cancer, but with limited expression in normal human tissues (1). CA125/MUC16 is the best known ovarian tumor-associated antigen and its secreted form has long been recognized as the gold standard for monitoring patients with ovarian carcinoma.
Role of Dendritic Cells in T Cell Immunity
Dendritic cells (DC) are rare but highly potent antigen presenting cells of bone marrow origin that can stimulate both primary and secondary T and B cell responses (19-24). The combination of two cytokines (i.e., GM-CSF and IL-4) has been shown to generate large numbers of myeloid monocyte-derived DC (9-24). However, after 6-8 days of culture in vitro these DC are still immature. Although they may effectively capture antigens, these immature DC lack full T cell-stimulatory activity and are sensitive to the immunosuppressive effects of several immunoregulatory cytokines that can be produced by tumors (25). In contrast, when maturation is induced by appropriate stimuli, such as monocyte-conditioned medium, LPS, or a cocktail of inflammatory cytokines (e.g., TNFα, IL1β, PGE2a) (26), DC demonstrate a reduced ability to phagocytose antigens, but show a significantly higher production of key cytokines (e.g., IL-12), increased resistance to the immunosuppressive effects of IL-10, increased expression of T cell adhesion and costimulatory molecules, and increased expression of chemokine receptors that guide DC migration into lymphoid organs for priming of antigen-specific T cells (24, 25).
DC and Human Tumor Immunotherapy
Monocyte-derived mature DC-based vaccinations have recently been shown to induce the rapid generation of broad T cell immunity in healthy subjects vaccinated with less than 3×106 antigen-pulsed autologous DC (27, 28). In contrast, the administration of immature DC has been reported to result in inhibition of pre-existing effector T cell function (29). These recently published studies represent the first indisputable evidence of the efficacy of DC vaccination as novel and powerful tools for human immunization. However, at this time, the extent to which general conclusions can be drawn from these observations for the active immunization of cancer patients remain only partially established.
In this regard, only a few clinical trials of DC vaccination have been reported in cancer patients. These studies have sometimes documented the induction of an anti-tumor immune responses and therapeutic benefit. In a study of patients with low grade, chemotherapy-resistant non-Hodgkin's lymphoma, four patients were given a series of subcutaneous injections of DC cultured with tumor-derived idiotype protein (30). All four patients developed lymphoproliferative responses to their own idiotype protein. Clinical responses were also seen, with one patient with pericardial and periaortic masses experiencing complete remission (durable for 42 months at the time of publication), and a second patient becoming PCR-negative (using idiotype-specific primers) and remaining in complete remission for 36 months. The remaining two patients showed stabilization of disease.
In children, vaccination of patients with solid tumors with tumor lysate-pulsed DC has been shown to expand tumor specific T cells and mediate cancer regression (35). Indeed, significant regression of multiple metastatic sites were seen in 1 patient. Five patients showed stable disease, including 3 who had minimal residual disease at the time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Only patients who had failed standard therapies and therefore had been heavily pretreated with chemotherapy were considered eligible for this study. Importantly, all pediatric patients were treated in an outpatient setting without any observable toxicity resulting by DC administration.
Treatments to prevent disease recurrence or progeression in ovarian and other cancers are needed.